Behavioral and Dopamine Transporter Binding Properties of the Modafinil Analog (S, S)-CE-158: Reversal of the Motivational Effects of Tetrabenazine and Enhancement of Progressive Ratio Responding

Rationale: Atypical dopamine (DA) transport blockers such as modafinil and its analogs may be useful for treating motivational symptoms of depression and other disorders. Previous research has shown that the DA depleting agent tetrabenazine can reliably induce motivational deficits in rats, as evidenced by a shift towards a low-effort bias in effort-based choice tasks. This is consistent with human studies showing that people with major depression show a bias towards low-effort activities. Objectives: Recent studies demonstrated that the atypical DA transport (DAT) inhibitor (S)-CE-123 reversed tetrabenazine-induced motivational deficits, increased progressive ratio (PROG) lever pressing, and increased extracellular DA in the nucleus accumbens. In the present studies, a recently synthesized modafinil analog, (S, S)-CE-158, was assessed in a series of neurochemical and behavioral studies in rats. Results: (S, S)-CE-158 demonstrated the ability to reverse the effort-related effects of tetrabenazine and increase selection of high-effort PROG lever pressing in rats tested on PROG/chow feeding choice task. (S, S)-CE-158 showed a high selectivity for inhibiting DAT compared with other monoamine transporters, and systemic administration of (S, S)-CE-158 increased extracellular DA in the nucleus accumbens during the behaviorally active time course, which is consistent with the effects of (S)-CE-123 and other DAT inhibitors that enhance high-effort responding. Conclusions: These studies provide an initial neurochemical characterization of a novel atypical DAT inhibitor, and demonstrate that this compound is active in models of effort-related choice. This research could contribute to the development of novel compounds for the treatment of motivational dysfunctions in humans. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature.The authors would like to acknowledge Eurofins DiscoverX Corporation (Fremont, CA)

Human and mouse essentiality screens as a resource for disease gene discovery.

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery

Human and mouse essentiality screens as a resource for disease gene discovery

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery. Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery

Complexities and paradoxes in understanding the role of dopamine in incentive motivation and instrumental action: Exertion of effort vs. anhedonia

Instrumental behavior is a very complex and multifaceted process. Behavioral output during instrumental performance is influenced by a variety of factors, including associative conditioning, directional and activational aspects of motivation, affect, action selection and execution, and decision-making functions. Detailed assessments of instrumental behavior can focus on the temporal characteristics of instrumental behavior such as local frequency and response duration, and biophysical measures of response topography such as force output over time. Furthermore, engaging in motivated behavior can require exertion of effort and effort-based decision making. The present review provides an overview of research on the specific deficits in operant behavior induced by dopamine antagonism and depletion. Furthermore, it discusses research on effort-based decision making, and highlights the complexities and seeming paradoxes that are revealed when detailed analyses of operant behavior are conducted, and instrumental behavior is put in the context of factors such as primary or unconditioned food reinforcement, appetite, binge-like eating, and response choice. Although impairments in mesolimbic dopamine are sometimes labeled as being due to “anhedonia”, a detailed deconstruction of the findings in this area of research point to a much more complex and nuanced picture of the role that dopamine plays in regulating instrumental behavior. Low doses of DA antagonists and accumbens dopamine depletions blunt the exertion of physical effort as measured by several different challenges in animal studies (e.g., lever pressing, barrier climbing, wheel running), and yet leave fundamental aspects of hedonic reactivity, food motivation, and reinforcement intact. Continued research on the specific features of instrumental behaviors that regulate the sensitivity to impaired dopamine transmission across a number of contexts is important for resolving some of the complexities that are evident in this area of inquiry. These investigations can also provide insights into psychomotor and motivational dysfunctions that are seen in neuropsychiatric conditions such as depression, schizophrenia, and Parkinson’s disease.This research was supported by grants to JS from the NIH (R01MH121350) and the University of Connecticut Research Foundation, to MC from MINECO (PSI2015-68497-R) Spain, and to CC (FPI BES-2016-077177). JS has received grants from, and done consulting work for, Shire, Prexa, Chronos, Blackthorn, Lundbeck, NOEMA, and Acadia. On behalf of all authors, the corresponding author states that there is no conflict of interest

PRE-SLEEP FEEDING IN NCAA DIVISION I FEMALE ATHLETES

Casey Greenwalt1, Lilliana Rentería1, Katherine Schiltz1, Elisa Angeles1, Abbie Smith-Ryan, FACSM2, Chris Bach3, Matthew Vukovich, FACSM4, Stacy Sims5, Tucker Zeleny3, Kristen Holmes6, David Presby7, Michael Ormsbee, FACSM1. 1Florida State University, Tallahassee, FL. 2University of North Carolina, Chapel Hill, NC. 3University of Nebraska, Lincoln, NE. 4South Dakota State University, Brookings, SD. 5Auckland University of Technology, Auckland. 6WHOOP, Inc., Boston, MA. 7WHOOP, Inc, Boston, MA. BACKGROUND: Due to the high metabolic demand of sport, it is essential that athletes meet their caloric need to support training, recovery, and muscle growth. Consuming protein (30-40g) before sleep may have positive effects on muscle protein synthesis, overnight recovery, and performance. Currently no data exists to assess pre-sleep nutrition habits in elite female athletes. PURPOSE: To examine the frequency and content of pre-sleep nutrition in elite female athletes. METHODS: 483 Division I female athletes (mean ± SD: age: 21.4 ± 2.5 yrs, weight 67.1 ± 10.2 kg, height 171.2 ± 8.9 cm) from four universities wore a WHOOP, Inc. band 24h a day for the entire 2020-2021 competitive season to measure activity, sleep, and recovery. Surveys were administered through the WHOOP app every 3 days over the season to collect data on pre-sleep feeding habits. Descriptive results were completed using R studio. RESULTS: 3741 pre-sleep feeding survey responses were recorded. Of that, 23.9% (n = 895) of the data was unusable as caloric content could not be determined due to insufficient data reported. The remaining 76.1% (n = 2846) of the survey responses were made up of 276 athletes, of which, 21% (n = 58) ate before bed more than once. The average pre-sleep food intake for n=58 consisted of total kcals (mean ± SD: 283.4 ± 68.8 kcals), protein (8.3 ± 3.2g; 11.5% of total kcals), carbohydrate (35.8 ± 13.0 g; 50.4% of total kcals), and fat (12.1 ± 3.8 g; 38.1% of total kcals). Percentage of each sport that ate before sleep was 24.1% soccer, 13.8% swimming, 12.2% cross country, 8.6% volleyball, 6.9% softball, 5.3% beach volleyball, 3.4% golf, lacrosse, and tennis, 1.7% basketball, and 17.2% the sport was not specified. CONCLUSIONS: This is the first study to investigate the self-reported frequency of pre-sleep feeding in a wide range of female sports at the NCAA Division I level. Of 483 female athletes in the study, only 58 users recorded that they ate before bed on more than one occurrence. Meals prior to bed primarily consisted of carbohydrate (50.4%) and fat (38.1%), with only 11.5% of pre-sleep kcals coming from protein. The impact of pre-sleep feeding on next-day performance and recovery is warranted. This study was supported by WHOOP, Inc

Measures of effect size

Two different approaches have been used to derive measures of effect size. One approach is based on the comparison of treatment means. The standardized mean difference is an appropriate measure of effect size when one is merely comparing two treatments, but there is no satisfactory analogue for comparing more than two treatments. The second approach is based on the proportion of variance in the dependent variable that is explained by the independent variable. Estimates have been proposed for both fixed-factor and random-factor designs, but their sampling properties are not well understood. Nevertheless, measures of effect size can allow quantitative comparisons to be made across different studies, and they can be a useful adjunct to more traditional outcome measures such as test statistics and significance levels